JP2012503015A - カルパイン阻害のための方法、系および組成物 - Google Patents
カルパイン阻害のための方法、系および組成物 Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/8139—Cysteine protease (E.C. 3.4.22) inhibitors, e.g. cystatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Psychiatry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
acc caa tgg cta cta cct acc taa gag gaa ttg ggt aaa aga gaa gtc aca att cct cca aaa tat agg gaa cta ttg gct (配列番号1)
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Ile Pro Pro Lys Tyr Arg Glu Leu Leu Ala (配列番号2)
Arg23からVal23
Glu24からAla24
Ala27からPro27、
Ser4-Ser5
Tyr6-Ile7
Lys13-Arg14
Glu15-Val16
Lys21-Tyr22
Tyr22-Arg23
Arg23-Glu24。
Ile18 → Nva18
Arg23 → Orn23、
次の配列を提供する。
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Nva Pro Pro Lys Tyr Orn Glu Leu Leu Ala (配列番号6)、
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Nva Pro Pro Lys Tyr Arg Glu Leu Leu Ala (配列番号7)、
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Ile Pro Pro Lys Tyr Orn Glu Leu Leu Ala (配列番号8);
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Nva Pro Pro Lys Tyr Val Ala Leu Leu Pro (配列番号9)、または
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Nva Pro Pro Lys Tyr Val Ala Leu Leu Pro Ala Val Leu Leu Ala Leu Leu Ala Pro (配列番号10)。
gcc gcg gta gcg ctg ctc ccg gcg gtc ctg ctg gcc ttg ctg gcg ccc (配列番号
NO: 11)
Ala Ala Val Ala Leu Leu Pro Ala Val Leu Leu Ala Leu Leu Ala Pro (配列番号12)。
タウリン、コレステロール、非イオン性両親媒性ジエチレングリコールメチル部分等などの非ペプチドBBB透過性構造を阻害剤に、場合により結合することもできる。
シグナル伝達、細胞遊走およびアポトーシス調節に重要な役割を果たすことが認められている重要なシステインプロテイナーゼであるカルパインの調節異常は、虚血性脳卒中後の組織損傷に関与している。本発明者らは、カルパインに特異的なカルパイン阻害剤を見出し、単離し、および/または作製した。
天然に存在するタンパク質であるカルパスタチンはカルパインに特異的な唯一の阻害剤であり、カルパスタチンとカルパインの相互作用が、Ca2+誘導タンパク質分解の調節を担う最も関連性のあるメカニズムであることが一般に受け入れられている。本発明者らは、カルパインの強力かつ特異的な阻害に重要な残基を含む、配列番号2のペプチドにおける2箇所の「ホットスポット」を同定した。本発明者らが知る限りにおいて、今日までに報告されたカルパインの薬理的阻害に関する研究で、カルパスタチンの絶対的特異性に利益を得て、虚血性脳卒中後にカルパインが細胞死および神経学的機能不全に寄与することを記したものはない。従って、本発明者らは、配列番号2の新規BBB透過性アナログの一実施形態である配列番号5を、ラットにおける局所性脳虚血後の脳梗塞および神経学的機能回復へのその効果について評価した。
動物モデル
施設承認の動物取扱いプロトコールに従い、雄のWistarラット(270〜290g)をCharles River Breeding Co.(ウィルミントン、マサチューセッツ州、米国)から入手した。血管内縫合法による2時間中大脳動脈閉塞(MCAO)、薬剤注入ならびに梗塞体積および神経学的欠失の測定は、前に詳述した通り行った。
MCAOと薬剤注入に続いて、動物を24または48時間の生存の後、屠殺した。この段階で脳を摘出し、右脳と左脳、皮質と皮質下領域に分離し、液体窒素中で手早く凍結して使用まで-80℃で保存した。ウエスタンブロット解析のため、脳サンプルをドライアイス上に置いた小型の乳鉢と乳棒で細末に粉砕した。0.025mM E-64、2.0mM AEBSF、0.5mM PMSF、0.02mMロイペプチン、0.05mMペプスタチンおよび0.001mMアプロチニンを含む0.25Mショ糖、25mM 2-(N-モルホリノ)-エタンスルホン酸、1mM EDTA、pH6.5(ホモジナイゼーションバッファー)溶液中で、粉砕した脳組織粉末を4℃でPotter-Elvehjemホモジナイザーにおいてホモジナイズした。次にホモジネートを4℃で20分間16,000gで遠心分離した。上清のアリコートを実験に使用するまで-80℃で保存した。micro BCAタンパク質アッセイキット(Pierce、ロックフォード、イリノイ州)を用いてタンパク質濃度を決定した。レムリ(Laemmli)法に従ってSDS-PAGEを行い、Towbinらの技法に従ってイムノブロットを行った。マウスモノクローナル抗αII-スペクトリン抗体(MAB1622、1:1,000)およびホースラディッシュペルオキシダーゼ(HRP)結合ヤギ抗マウスIgG(AP124P、1:10,000)は、Chemicon(テメクラ、カリフォルニア州)から入手した。増強化学発光(enhanced chemiluminescence)法を用いて、メーカーの取扱説明書(GE Healthcare Biosciences、ピスカタウェイ、ニュージャージー州、米国)に従って標識タンパク質を検出した。Gel-Doc2000(Bio-Rad、リッチモンド、バージニア州)およびフリーオープンソースのソフトウェアImageJ(http://rsb.info.nih.gov/ij/)を用いてデンシトメトリーによりバンドを定量化した。
梗塞体積
H&E切片から、好酸球性バックグラウンドのびまん性蒼白を有する虚血中心領域と、空胞形成すなわち海綿化(sponginess)および好中球を有する境界領域とを顕微鏡下で確認することができる。図3における代表的なH&E染色連続冠状断面A〜Gから分かるように、虚血により大部分が病変した脳領域は、MCA分布における皮質である(黒矢印)。中心薄切片CおよびDにおける皮質下領域も病変している(白矢印)。虚血性損傷(すなわち、細胞死、組織の減失または脳軟化症)は、ビヒクル処置対照と比べて配列番号5処置動物では少なかった。比較したところ、対側は肉眼による検査と組織切片の両方により損傷を受けていないように見えた。Table 1(表1)および図1に示すように、配列番号5は、それぞれ配列番号13処置(24.9±3.8%vs.33.8±4.2%、脳半球の梗塞体積パーセント±SE;#P<0.05、独立t-検定;n=9/群)およびビヒクル処置(24.9±3.8%vs.38.4±2.1%、脳半球の梗塞体積パーセント±SE;*P<0.05、独立t-検定;n=9/群)対照と比べて梗塞体積を顕著に低減させた。
神経学的スコアは、以前に次の通り定義された。観察可能な欠失なし=0、前肢屈曲=1、側方の圧力に対する抵抗力の低下と前肢屈曲=2、2と同じ行動+旋回=3。行動データは、傷害後最初の4日間で全ての実験群において神経学的スコアが僅かに改善したことを示している(Table 1(表1)および図2)。しかし、配列番号5処置動物とビヒクル対照との間(1.00±0.17vs.1.78±0.22、*P<0.05、n=9/群;独立t-検定)、また配列番号13処置群との間(1.00±0.17vs.1.44±0.18、#P<0.05、n=9/群;独立t-検定)における動作の差異は、傷害後7日目では統計的に有意であった。
カルパインの病的活性および配列番号5のin vivoにおける有効性を、MCAO後にラット脳で生じたαII-スペクトリン分解産物(SBDP)のウエスタンブロット解析により評価した。図4は、配列番号5が、MCAO後のラット脳においてカルパインによるαII-スペクトリン分解を遮断することを表すデータを示す。(A〜D)MCAO後24時間(A、B)および48時間(C、D)における、偽手術、虚血ビヒクル処置および虚血配列番号5処置動物の同側皮質(A、C)および皮質下(B、D)領域の、αII-スペクトリンの代表的なイムノブロット。完全αIIスペクトリン(280kDa)、SBDP150、SBDP145、SBDP120およびSBDP110を示す。(E) MCAO後24および48時間における同側皮質および皮質下におけるSBDP150/SBDP145レベルのデンシトメトリー解析。
本発明者らは、配列番号5を用いて脳卒中後の神経血管機能不全におけるカルパインの役割を調査した。
配列番号5の虚血後投与は、未処置動物と比べて梗塞体積および神経学的欠失をそれぞれ35%および44%低下させた(それぞれp<0.05)。アルブミンとフィブリンの血管外漏出により評価したBBB完全性は、48時間で対照と比べて配列番号5処置後に有意な改善を示した(p<0.05)。脳卒中後の脳で高度にアップレギュレート(約3倍)されることが認められている内皮一酸化窒素合成酵素(eNOS)のスレオニン-495リン酸化は、配列番号5での処置によって顕著に抑制された。従って、本発明者らは、特異的なカルパスタチンに基づくカルパイン阻害剤を用いた一過性脳虚血の治療が、BBB完全性におけるその有益な影響から分かるように、eNOS調節および血管保護作用に関連する神経保護および機能回復をもたらすことを思いがけず見出した。
開示される核酸配列とペプチド配列
配列番号1:
acc caa tgg cta cta cct acc taa gag gaa ttg ggt aaa aga gaa gtc aca att cct cca aaa tat agg gaa cta ttg gct
配列番号2:
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Ile Pro Pro Lys Tyr Arg Glu Leu Leu Ala
配列番号3:
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Ile Pro Pro Lys Tyr Val Ala Leu Leu Pro
配列番号4:
Ala Val Leu Leu Ala Leu Leu Ala Pro
配列番号5:
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Ile Pro Pro Lys Tyr Val Ala Leu Leu Pro Ala Val Leu Leu Ala Leu Leu Ala Pro
配列番号6:
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Nva Pro Pro Lys Tyr Orn Glu Leu Leu Ala
配列番号7:
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Nva Pro Pro Lys Tyr Arg Glu Leu Leu Ala
配列番号8:
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Ile Pro Pro Lys Tyr Orn Glu Leu Leu Ala
配列番号9:
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Nva Pro Pro Lys Tyr Val Ala Leu Leu Pro
配列番号10:
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu Leu Gly Lys Arg Glu Val Thr Nva Pro Pro Lys Tyr Val Ala Leu Leu Pro Ala Val Leu Leu Ala Leu Leu Ala Pro
配列番号11:
gcc gcg gta gcg ctg ctc ccg gcg gtc ctg ctg gcc ttg ctg gcg ccc
配列番号12:
Ala Ala Val Ala Leu Leu Pro Ala Val Leu Leu Ala Leu Leu Ala Pro
配列番号13:
Asp Pro Met Ser Ser Thr Tyr Ile Glu Glu βAla Gly Lys Arg Glu Val Thr Ile Pro Pro Lys Tyr Val Ala Leu Leu Pro Ala Val Leu Leu Ala Leu Leu Ala Pro
Claims (21)
- 配列番号5を含む合成ペプチド。
- 配列番号5を含む組成物。
- 請求項2に記載の組成物を提供するステップと、
医薬的有効量の前記組成物を哺乳類に投与するステップと、
を含む、虚血イベントに続く哺乳類の神経損傷を抑制する方法。 - 哺乳類がヒトである、請求項3に記載の方法。
- 虚血イベントに続く哺乳類の神経損傷を抑制するための薬剤における、配列番号5の使用。
- 哺乳類がヒトである、請求項5に記載の使用。
- 配列番号3、5、6、7、8、9および10のうち1つまたは複数を含む組成物。
- 請求項7に記載の組成物を提供するステップと、
医薬的有効量の前記組成物を哺乳類に投与するステップと、
を含む、虚血イベントに続く哺乳類の神経損傷を抑制する方法。 - 哺乳類がヒトである、請求項8に記載の方法。
- 虚血イベントに続く哺乳類の神経損傷を抑制するための薬剤における、配列番号3、5、6、7、8、9および10のうち1つまたは複数の使用。
- 哺乳類がヒトである、請求項11に記載の使用。
- 配列番号2または配列番号5を含む合成ペプチドであって、前記配列における次のアミノ酸対:Ser4-Ser5、Tyr6-Ile7、Lys13-Arg14、Glu15-Val16、Lys21-Tyr22、Tyr22-Arg23のうち1つまたは複数のペプチド結合が非ペプチド性還元アミド結合で置換されている、合成ペプチド。
- 請求項12に記載の合成ペプチドを含む組成物を提供するステップと、
医薬的有効量の前記組成物を哺乳類に投与するステップと、
を含む、虚血イベントに続く哺乳類の神経損傷を抑制する方法。 - 哺乳類がヒトである、請求項13に記載の方法。
- 虚血イベントに続く哺乳類の神経損傷を抑制するための薬剤における、請求項12に記載の合成ペプチドの使用。
- 哺乳類がヒトである、請求項15に記載の使用。
- Lys21とGlu24との間に側鎖環化が存在する、配列番号2を含む合成ペプチド。
- 請求項17に記載の合成ペプチドを含む組成物を提供するステップと、
医薬的有効量の前記組成物を哺乳類に投与するステップと、
を含む、虚血イベントに続く哺乳類の神経損傷を抑制する方法。 - 哺乳類がヒトである、請求項18に記載の方法。
- 虚血イベントに続く哺乳類の神経損傷を抑制するための薬剤における、請求項17に記載の合成ペプチドの使用。
- 哺乳類がヒトである、請求項20に記載の使用。
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JP2015061874A (ja) * | 2008-09-19 | 2015-04-02 | ヘンリー フォード ヘルス システムHenry Ford Health System | カルパイン阻害のための方法、系および組成物 |
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